Sj?gren's syndrome (SjS) is an autoimmune disease characterized primarily by exocrine gland dysfunction, specifically of the salivary and lacrimal glands, resulting in dry mouth and dry eyes symptoms. It can be systemic by affecting other organs including the gastrointestinal tract, skin, lungs, vasculature, kidneys, bladder and vagina. Involvement of the musculature can lead to fibromyalgia-like symptoms and chronic fatigue, while approximately 20% of patients develop various neuropathies, including sensory, peripheral, cranial and myelopathic neuropathies exhibited by cognitive impairments such as dementia, lack of concentration, memory loss and various psychiatric disorders. Like most autoimmune connective tissue diseases, SjS shows a sexual dimorphism with women affected 10-times more frequently than men, suggesting a role for sex hormones in disease susceptibility or progression. One common feature of SjS in both humans and animal models is infiltration of mononuclear cells into the salivary and lacrimal glands, aggregating into clusters referred to as lymphocytic foci (LF). Critical to the studies proposed in the current grant application is the fac that a predominant cell population of LF is the pathogenic TH17 cell that produces IL-17 cytokine. To date, virtually nothing is known about the receptors of these infiltrating TH17 cells (or the ligands these receptors recognize). Using an innovative and novel technology called microengraving designed for high-throughput single cell analysis, this study aims to provide proof of concept data that, through identifying the TH17 receptor(s) of this infiltrating cell population, we will be able to develop a blocking (or cytotoxic) antibody therapeutic reagent capable of preventing the pathogeneic TH17 cell population(s) specific to SjS from migrating to the exocrine glands and eliciting subsequent glandular dysfunction. To achieve this goal, we propose to define the oligoclonal nature of the salivary gland-infiltrating TH17 cell population. B utilizing microengraving technology, we will analyze large numbers of individual cells, determine the frequency and profiles of the TH17 cell population(s) infiltrating the salivary glands of C57BL/6.NOD-Aec1Aec2 mice and the labial salivary glands of primary SjS patients. We will then apply high-throughput sequencing technology to define the diversity of the TH17 TCR?? gene repertoires for both mouse and human TH17 cells involved in SjS. Performing these studies simultaneously in both SjS mouse models (a homogeneous disease) and primary SjS patients (a highly heterogeneous disease) is expected to further our understanding of the role of TH17 cells in this disease. Results of the proposed study are anticipated to provide a clearer understanding of the autoimmune process mediated by TH17 cells and their TCR repertories, while on a more fundamental level, establish the direction to move this approach forward for generating and testing an appropriate anti-idiotype reagent(s) for blocking the function of SjS-specific TH17 cells. Such an inventive approach in target killing or inhibition of the pathogenic and autoimmune TH17 cells could pave the way for future personalized medicine of a disease that has thus far proven refractive to all other interventions.